V-Set Immunoglobulin Domain–Containing Protein 4 as a Novel Serum Biomarker of Lupus Nephritis and Renal Pathology Activity

Objective: To discover novel serum biomarkers that have diagnostic or predictive value in lupus nephritis (LN). Methods: Using a quantitative protein microarray, we screened for high-abundant proteome expression in the serum of patients with LN compared to healthy controls. Top candidates from this screening were validated using a larger cohort of patients with LN compared to a disease control cohort (subjects with other chronic kidney diseases) and a healthy control cohort. Promising markers were then selected using a machine-learning model and further validated with a larger patient cohort. The corresponding autoantibodies and immune complexes containing these proteins were also examined. Results: In total, 13 proteins were found to be significantly elevated in LN patient serum in the screening, among which 8 proteins were validated by enzyme-linked immunosorbent assay using 81 serum samples from LN patients and control subjects. Three serum markers with LN diagnostic potential were identified using feature importance analysis and further validated using 155 serum samples from LN patients and control subjects. V-set immunoglobulin domain–containing protein 4 (VSIG4) appeared to be the most promising marker in distinguishing LN from healthy controls, with an area under the curve of 0.93. VSIG4 could also discriminate active LN from inactive LN. Furthermore, serum VSIG4 levels were positively correlated with all of the following clinical parameters: the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score (Spearman's rank correlation r_s = 0.42, P < 0.001), the renal domain score of the SLEDAI (r_s = 0.46, P < 0.001), the urinary protein-to-creatinine ratio (r_s = 0.56, P < 0.001), and the serum creatinine level (r_s = 0.41, P < 0.001). Importantly, we found that serum VSIG4 levels tracked with LN disease activity longitudinally, and that serum VSIG4 levels reflected the renal pathology activity index (AI), particularly the AI components of crescent formation and hyaline deposits. Conclusion: VSIG4 may be a promising novel serum biomarker and therapeutic target in patients with LN. (Figure presented.).